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Thrombocytopenia in the Intensive Care Unit Ming S. He, M.D. Platelet Counts Normal: 150,000 – 450,000 /μL Thrombocytopenia: Less than 150,000 /μL Beware of dramatic decline in platelet count even if the count is still within normal range Surgical bleeding is a risk when PLT (platelet) is less than 50,000 /μL Spontaneous bleeding is a risk when PLT is less than 10,000 – 20,000 /μL Platelet Kinetics Produced in the bone marrow by megakaryocytes via cytoplasmic shedding Circulate for 8-10 days then removed by monocytemacrophage system “Young platelets” are more hemostatically active 1/3 of PLTs in normal individual found in spleen Mechanisms of Thrombocytopenia Decreased PLT production Viral Infections: HIV, hepatitis C, EBV, parvovirus, rubella, mumps, and varicella Chemotherapy and radiation therapy Congenital and Acquired bone marrow aplasia / hypoplasia Acute Leukemias Vitamin B12 and folic acid deficiency Mechanisms of Thrombocytopenia Increased PLT destruction Immune mediated ITP HIV Antiphospholipid syndrome Drugs TTP-HUS (thrombotic thrombocytopenic purpurahemolytic uremic syndrome) Physical destruction of PLT (cardiopulmonary bypass, large aortic aneurysms, and/or intra-aortic balloon pump) Mechanisms of Thrombocytopenia Dilutional thrombocytopenia occurs after large volume transfusion after massive blood loss Splenomegaly can cause increase sequestration of PLTs in the spleen by up to 90%. Clinical bleeding is rare as total available PLT mass is normal Pseudothrombocytopenia Blood sample inadequately anticoagulated EDTA induced platelet clumping present in 0.1% of normal population Thrombocyopenia in the ICU Often multi-factorial DIC (disseminated intravascular coagulation) Post transfusion purpura ARDS (adult respiratory distress syndrome) Intra-aortic balloon pump Drugs/Heparin Infection/sepsis Shock Cardiopulmonary bypass Use of intravascular catheters TTP Evaluation of Thrombocytopenia History Physical exam Abdominal exam Rectal exam Fundascopic exam Skin exam Peripheral Smear Bone Marrow Aspiration DIC Sepsis The likely culpurits Shock Trauma/Extensive Surgery Meningococemia Gram negative bacteremia (DIC in 30-50% of patients) Gram postitive bacteremia (Staph aureus, Strep pneumoniae, Clostridia perfringens) Fungemia Severe head injury Malignancy Obstetrical complications DIC Results from massive activation of clotting cascade Increase in thrombin formation causes widespread aggregation of PLTs and fibrin deposition Compensatory generation of plasmin in the setting of diffuse thrombosis causes thrombolysis and mass release of fibrinogen degradation products (FDP). Plasmin also cause proteolytic degradation of other clotting factors causing coagulopathy. FDP interferes with normal fibrin polymerization and platelet aggregation DIC Laboratory values Reduced PLT count Prolonged PT, PTT Reduced plasma fibrinogen Elevated FDP Elevated D-dimer DIC Peripheral Smear reveals schistocytes, helmet cells Drug Induced Thrombocytopenia Usually by accelerating PLT destruction via drugdependent anti-platelet antibodies Drug binds to platelet surface glycoproteins (GPIbIX, GPIIB-IIIa) causing conformational change and exposing neoepitope that serves as target for antibodies The drug is generally a part of the neoepitope Drug-dependent anti-platelet antibodies are very specific and usually do not cross react with other drugs of the same class Drug Induced Thrombocytopenia Diagnosis is made when thrombocytopenia resolves after the suspected drug is discontinued Median for PLT count recovery after discontinuation of drug is 5-7 days Assays for drug-dependent antiplatelet antibodies not readily available If PLT is less than 10,000 /μL or bleeding occurs, treat with steroids as well as transfusion incase of ITP Drug Induced Thrombocytopenis The mostly likely culpurits include Quinine Quinidine Valproic acid Ranitidine Rifampin Trimethoprim-sulfamethoxazole GPIIbIIIa inhibitors Heparin Some of the others… GPIIb/IIIa Inhibitor Induced Thrombocytopenia True thrombocytopenia Most common with abciximab Less common with tirofiban and eptifibatide Occurs within 24 hours When GPIIbIIIa inhibitors bind PLT neoepitopes are exposed and induce antibody formation Thrombocytopenia can occur within 30 minutes of abciximab administration because of naturally occurring preformed antibodies GPIIb/IIIa Inhibitor Induced Thrombocytopenia Analysis from the TARGET (tirofiban or abciximab before PCI) trial showed patients with thrombocytopenia More frequent severe bleeding Higher incidence of death Higher incidence of MI Higher incidence of need from target vessel revascularization at 30 days GPIIb/IIIa Inhibitor Induced Thrombocytopenia Pseudothrombocytopenia Pseudothrombocytopenia occurs in 2% of patients exposed to abciximab Not associated with adverse outcome Results from a naturally occurring platelet autoantibody against a normally concealed epitope of GPIIbIIIa which become exposed after exposure to EDTA PLT count should be normal when heparin or sodium citrate is used Pseudothrombocytopenia Heparin-Induced Thrombocytopenia Type I A relatively mild fall in PLT count within first 2 days of heparin initiation; PLT count often remains in the normal range PLT count often returns to normal with continued heparin administration Non-immune mediated No clinical consequence Heparin-Induced Thrombocytopenia Incidence of immune mediated HIT occurs in 0.3-3% of patients exposed to heparin for more than 3 days Pathophysiology Heparin binds platelet factor 4 (PF4) and a conformational change occurs which forms an epitope recognized by most HIT antibodies (IgG and IgM) Heparin-PF4-antibody complex leads to platelet activation which leads to further release of PF4 Activated PLT aggregate and leads to thrombosis as well as thrombocytopenia Heparin-Induced Thrombocytopenia Thrombocytopenia is usually not severe with PLT count between 20,000 – 60,000/μL Spontaneous bleeding is rare Delayed onset HIT is the development of thrombosis and thrombocytopenia after heparin has been withdrawn. Has been documented to occur between 9 to 40 days after last exposure to heparin Mechanism is unclear Heparin-Induced Thrombocytopenia Patients with HIT can develop venous and arterial thrombosis Events include DVT Venous limb gangrene PE Stroke MI Organ infarction Limb ischemia Unusual complications of HIT Adrenal hemorrhage Transient global amnesia Heparin-Induced Thrombocytopenia Clinical diagnosis Diagnostic tests 14 C serotonin release assay Heparin-induced PLT aggregation assay 100% sensitivity, 97% specificity Very expensive and technically difficult Less than 80% sensitivity, 90% specificity Solid phase immunoassay (ELISA immunoassay to detect presence of heparin dependent antibodies) 91% sensitivity, very low specificity Heparin-Induced Thrombocytopenia Treatment Cessation of all heparin exposure Use of lepirudin/bivalirudin or argatroban (direct thrombin inhibitor) for anticoagulation until PLT count has recovered Initiate warfarin after a patient is stably anticoagulated Other agents Fondaparinux Danaparoid Patients with a history of HIT who require cardiopulmonary bypass who are antibody negative at the time of surgery do not generally develop complications with the brief heparin exposure Post Transfusion Purpura Severe thrombocytpenia 5 to 10 days after transfusion of PLT containing product and recovery occurs between days 7 to 48. Occurs primarily in women who had prior exposure/sensitization to foreign antigen Antigen most commonly implicated is HPA 1a Patients’ own PLTs are HPA 1a negative, but are also destroyed in PTP via unclear mechanism Treatment is IVIG or plasma exchange PLT transfusion is NOT effective TTP-HUS Characteristics Thrombocytopenia Microangiopathic hemolytic anemia Neurologic signs and symptoms Renal function abnormalities Fever Pathology Thrombi composed mainly of PLT ADAMTS13 deficiency Plasminogen activator inhibitor (inhibits fibrinolysis) Lack of PLT inhibitor TTP-HUS Etiology Idiopathic Endothelial injury Shiga like toxin (E. coli) Drugs Most notably quinine Cancer/Chemotherapy Antiphospholipid antibody/SLE Pregnancy/Post Partum Immunosuppressive agents (cyclosporin) Antiplatelet agents (ticlopidine, clopidegrol) HIV/HAART TTP Clinical diagnosis Schistocytes on peripheral smear Normal PT/PTT Treatment Renal failure and death if untreated Remove precipitating factor if possible Plasma exchange until PLT returns to normal Add steroids if poor response Dialysis if necessary Follow patients for relapse When all else fails? Heme/Onc Consult References www.uptodate.com Thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion requirements, and outcome. Strauss R - Crit Care Med - 01-AUG-2002; 30(8): 1765-71 From NIH/NLM MEDLINE Delayed-onset heparin-induced thrombocytopenia. Smythe MA - Ann Emerg Med - 01-APR-2005; 45(4): 417-9 From NIH/NLM MEDLINE Hoffman: Hematology: Basic Principles and Practice, 4th ed., Copyright © 2005 Elsevier Disseminated Intravascular Coagulation: What's New? Critical Care Clinic Volume 21 • Number 3 • July 2005 Disseminated intravascular coagulation current concepts of etiology, pathophysiology, diagnosis, and treatment. Bick RL - Hematol Oncol Clin North Am - 01-FEB-2003; 17(1): 149-76 Critical issues in hematology: anemia, thrombocytopenia, coagulopathy, and blood product transfusions in critically ill patients. Drews RE - Clin Chest Med - 01-DEC-2003; 24(4): 607-22 From NIH/NLM MEDLINE Current concepts in the diagnosis and management of thrombotic thrombocytopenic purpura. Nabhan C Hematol Oncol Clin North Am - 01-FEB-2003; 17(1): 177-99 From NIH/NLM MEDLINE HIV: clinical manifestations. Moylett EH - J Allergy Clin Immunol - 01-JUL-2002; 110(1): 3-16 From NIH/NLM MEDLINE